The present invention relates to hydroxyalkyl-substituted pyrimidines having a fused cyclopropane ring in the hydroxyalkyl side chain and the heterocyclic isosteres of said pyrimidines, and to processes for preparing such compounds. These compounds have antiviral acitivity, and are particularly effective against herpes viruses, e.g., herpes simplex virus.
The compounds of the invention may be represented by the formula, ##STR1## (and the pharmaceutically acceptable salts thereof), wherein Y is a pyrimidin-1-yl or a hetercyclic isostere of a pyrimidin-1-yl group; R.sup.1 is selected from hydrogen and alkyl of 1-to-4 carbon atoms; R.sup.2 is selected from hydrogen, alkyl of 1-to-4 carbon atoms and --CH.sub.2 OH; and Z is &gt;CH.sub.2 or &gt;O.
Preferably, Y is cytosine, uracil or thymine.
An isostere is a molecule which is isosteric with another molecule; that is, has a similarity of structure and a resulting similarity of properties exhibited by the molecules. The molecules may contain different atoms and not necessarily the same number of atoms, but possess the same total or valence selections in the same arrangement, viz., carbon monoxide (C.dbd.O) and atmospheric nitrogen (N.dbd.N), or cyanide ion (--C.tbd.N) and acetylide ion (--C.tbd.CH). Some heterocyclic systems isosteric with oxopyrimidines include 3-deazauracil (e.g. 2,4-dihydroxypyridine), 6-azauracil (e.g. 3,5-dihydroxy-1,2,4-triazine), and 5-azacytosine (2-amino-4-hydroxy-1,3,5-triazine).
The following are representative compounds of the present invention:
1-[(E)-2-(Hydroxymethyl)cyclopropylmethyl]thymine PA0 1-[(Z)-2-(Hydroxymethyl)cyclopropylmethyl]thymine PA0 1-[(E)-2-(Hydroxymethyl)cyclopropylmethyl]uracil PA0 1-[(Z)-2-(Hydroxymethyl)cyclopropylmethyl]uracil PA0 1-[(Z)-2-(Hydroxymethyl)cyclopropylmethyl]cytosine PA0 1-[(Z)-2-(Hydroxymethyl)cyclopropylmethyl]cytosine PA0 1-[2,2-Bis(hydroxymethyl)cyclopropylmethyl]thymine PA0 1-[2,2-Bis(hydroxymethyl)cyclopropylmethyl]uracil PA0 1-[(E)-2,3-Epoxy-4-hydroxybutyl]thymine PA0 1-[(Z)-2,3-Epoxy-4-hydroxybutyl]thymine PA0 1-[(E)-2,3-Epoxy-4-hydroxybutyl]uracil PA0 1-[(Z)-2,3-Epoxy-4-hydroxybutyl]uracil PA0 1-[(E)-2-Hydroxymethyl-1,2-dimethylcyclopropylmethyl]thymine PA0 1-[(Z)-2-Hydroxymethyl-1,2-dimethylcyclopropylmethyl]thymine PA0 1-[(E)-2-Hydroxymethyl-1,2-dimethylcyclopropylmethyl]uracil PA0 1-[(Z)-2-Hydroxymethyl-1,2-dimethylcyclopropylmethyl]uracil PA0 1-[(E)-2-(Hydroxymethyl)cyclopropylmethyl]cytosine PA0 1-[(Z)-2-(Hydroxymethyl)cyclopropylmethyl]cytosine PA0 1-[(2,2)-Bis(hydroxymethyl)cyclopropylmethyl]cytosine PA0 1-[(E)-2,3-Epoxy-4-hydroxybutyl]cytosine PA0 1-[(Z)-2,3-Epoxy-4-hydroxybutyl]cytosine PA0 1-[(E)-2-Hydroxymethyl-1,2-dimethylcyclopropylmethyl]cytosine, and PA0 1-[(Z)-2-Hydroxymethyl-1,2-dimethylcyclopropylmethyl]cytosine. PA0 1-[(Z)-2-(Hydroxymethyl)cyclopropylmethyl]thymine PA0 1-[(Z)-2-(Hydroxymethyl)cyclopropylmethyl]uracil PA0 1-[(Z)-2-(Hydroxymethyl)cyclopropylmethyl]cytosine
The following compounds are preferred:
The compounds of the present invention may be prepared by various methods, as represented by the following schemes: ##STR2##
According to one method (Scheme I), which is similar to that of Noell et al., J. Med. Pharm. Chem., 5, 558 (1962), 6-chloroisocytosine [2-amino-6-chloro-4(3H)-pyrimidinone], a compound within the genus of Formula I, is reacted with an excess amount of the appropriate amino alcohol of Formula II. The reaction is conducted at elevated temperature in a suitable high boiling, polar solvent, preferably 2-ethoxyethanol, at reflux. Preferably, about three equivalents of the compound of Formula II are used per equivalent of the compound of Formula I, but a lesser amount of the compound of Formula II, preferably from about 1.5 to 2 equivalents, may be used if a compatible base, such as a high-boiling tertiary aliphatic amines, e.g., 1,4-diazabicyclo[2.2.2]-octane (DABCO), is added to the reaction mixture to scavenge the HCl liberated during the reaction. The reaction is run for from about 1 to about 18 hours, preferably for from about 1 to about 3 hours, and the resulting 6-(hydroxyalkylamino)isocytosine of Formula III may be isolated.
Isosteres of compounds of Formula III may then be prepared by known methods.
The 1-substituted pyrimidines of Formula VI may also be prepared (Schemes II) by alkylation of a preformed pyrimidine derivative of Formula IV (e.g., 5-azacytosine, pertrimethylsilyl-uracil, pertrimethylsilyl-thymine, 2,4-dimethoxypyrimidine, or N.sup.4 -acetylcytosine) with a compound of Formula V, wherein X is a leaving group, such as bromo, chloro, iodo, tosyl, mesyl and the like, and Q is a protecting group removable by hydrolysis, such as, for example, benzoyl or acetyl, or by hydrogenolysis such as, for example, benzyl. The alkylation may be carried out in the presence of a base such as, for example, potassium carbonate or sodium hydride, in a suitable solvent such as, for example, dimethylformamide or dimethylsulfoxide, or it may be carried out in these solvents without additional base. The 1-alkylated product of Formula VI may be separated from any isomers chromatographically or by other means. Transformation of the substituents Z and W, and removal of the protecting group Q may be accomplished by standard methods known to those skilled in the art.
Scheme III then illustrates the preparation of, e.g., 1-[(Z)-2-(hydroxymethyl)cyclopropylmethyl]cytosine, by the addition of chloromethylcyclopropane VIII to a pyrimidine of Formula VII. Chloromethylcyclopropanes may also be used to alkylate other pyrimidines of this invention or other isosteric heterocyclic systems. Such alkylations may be accomplished in the presence of sodium iodide and a base, such as potassium carbonate, in a polar solvent, such as dimethyl sulfoxide or dimethyl formamide, preferably at a temperature of about 70.degree. to 90.degree. C. The resulting alkylated pyrimidines may then be purified by chromatography and the benzoyl protecting group may be removed by standard conditions, such as aqueous methylamine, methanolic ammonia, or catalytic sodium methoxide in methanol.
Synthetic scheme II is also readily amenable to the synthesis of isosteric oxypyrimidine compounds by simply substituting the appropriately-preformed isosteric heterocycle for the oxypyrimidine which undergoes the alkylation reaction.
Pharmaceutically-acceptable salts are prepared by recrystallization of the desired cytosine, uracil or thymine derivative as the free base or as the acetate or hydrochloride from the aqueous dilute acid of choice. Alkali metal salts of thymine and uracil derivatives may be made by standard techniques, for example, by dissolving such derivative in water containing one equivalent of an alkali metal hydroxide, followed by evaporation to dryness.
In another aspect of the invention there is provided a pharmaceutical composition or preparation comprising a compound of the formula ##STR3## wherein Y, Z, R.sup.1 and R.sup.2 are as hereinbefore defined; or a pharmaceutically-acceptable salt thereof, together with a pharmaceutically-acceptable carrier therefor. In a particular aspect the pharmaceutical composition comprises a compound of the present invention in effective unit dosage form.
As used herein the term "effective unit dosage" or "effective unit dose" is denoted to mean a predetermined antiviral amount sufficient to be effective against the viral organisms in vivo. Pharmaceutically-acceptable carriers are materials useful for the purpose of administering the medicament, and may be solid, liquid or gaseous materials, which are otherwise inert and medically acceptable and are compatible with the active ingredients.
These pharmaceutical compositions may be given parenterally, orally, used as a suppository or pessary, applied topically as an ointment, cream, aerosol, powder, or given as eye or nose drops, etc., depending on whether the preparation is used to treat internal or external viral infections.
For internal infections the compositions are administered orally or parenterally at dose levels of about 0.1 to 250 mg per kg, preferably 1.0 to 50 mg per kg of mammal body weight, and are used in man in a unit dosage form, administered, e.g. a few times daily, in the amount of 1 to 250 mg per unit dose.
For oral administration, fine powders or granules may contain diluting, dispersing and/or surface active agents, and may be presented in a draught, in water or in a syrup; in capsules or sachets in the dry state or in a non-aqueous solution or suspension, wherein suspending agents may be included; in tablets, wherein binders and lubricants may be included; or in a suspension in water or a syrup. Where desirable or necessary, flavoring, preserving, suspending, thickening or emulsifying agents may be included. Tablets and granules are preferred, and these may be coated.
For parenteral administration or for administration as drops, as for eye infections, the compounds may be presented in aqueous solution in a concentration of from about 0.1 to 10%, more preferably 0.1 to 7%, most preferably 0.2% w/v. The solution may contain antioxidants, buffers, etc.
Alternatively, for infections of the eye, or other external tissues, e.g. mouth and skin, the compositions are preferably applied to the infected part of the body of the patient as a topical ointment or cream. The compounds may be presented in an ointment, for instance, with a water soluble ointment base, or in a cream, for instance with an oil in water cream base, in a concentration of from about 0.1 to 10%, preferably 0.1 to 7%, most preferably 1% w/v.